Anthelmintic compounds

ABSTRACT

The compound of formula (I)   wherein R and R1 are the same or different and each is hydrogen, an optionally substituted aliphatic hydrocarbon group having 1 to 7 carbon atoms, or an unsaturated aliphatic hydrocarbon group having 2 to 4 carbon atoms; R2 and R3 are the same or different and each is hydrogen or an alkyl group having 1 to 4 carbon atoms; Z is the group v,4/4 WHERE M IS 0 OR 1, AND X, X1 and X2 are the same or different and each is hydrogen or an alkyl group having 1 to 3 carbon atoms; and A is 1) a carbonyldioxy group (-O-CO-O-) or is a divalent residue of a monocarboxylic acid or a dicarboxylic acid containing 2 to 14 carbon atoms and having two ester linkages, or one ester and one ether linkage, to the rest of the molecule. The compounds are useful in the treatment of liver fluke infections of mammals.

United States Patent 1 1 Harfenist 1 Dec. 3, 1974 1 i ANTHELMINTIC COMPOUNDS [75] Inventor: Morton Harfenist, Chapel Hill, NC.

[73] Assignee: Burroughs Wellcome Co., Triangle Park, NC.

22 Filed: Feb. 25, 1972 211 Appl. No: 229,563

[52} US. CL... 260/485 J, 260/293.78, 260/293.86, 260/3322 C, 260/3475, 260/404.5,

260/463, 260/468 K, 260/471 R, 260/475 R, 260/475 SC, 260/482 R, 260/562 A,

[51 Int. Cl. C07c 69/40, C07c 69/48 [58] Field of Search 260/485 .1

[56] References Cited OTHER PUBLICATIONS Dickerson et al., Br. Vet. J., 127, x1, pg, 1041, (1971),

Primary Examiner-Lorraine AJWeinberger Anus/stunt ExaminerE Jane Skelly Armrney, Agent, or Firm-Dike, Bronstein, Roberts, C ushman & Pfund [57] ABSTRACT The compound of formula (1) wherein R and R are the same or different and each is hydrogen, an optionally substituted aliphatic hydrocarbon group having 1 to 7 carbon atoms, or an unsaturated aliphatic hydrocarbon group having 2 to 4 'carbon atoms; R and R are the same or different and each is hydrogen or an alkyl group having 1 to 4 can bon atoms; Z is the group 1 1a lie 1,.

5 Claims, N0 Drawings ANTHlELMllNTllC (IOMIPOUNDS This invention relates to esters, their synthesis. formulations containing them and their use in the treatment of liver fluke infections in mammals.

Animals are infected with liver fluke when eating forage contaminated with encysted forms of cercariac, an intermediate stage in the lifecycle of the fluke. The cercariae emerge from the cysts in the intestine of the host animal, penetrate the intestine wall, and make their way to the liver. At this stage they are microscopic in size, but grow as they wander around the liver paren chyma. This causes considerable destruction of the liver tissue and can give rise to the syndrome of acute fascioliasis which normally leads to death of the host when massive infections are present. If the animal survives, the flukes eventually reach the bile ducts where they mature into the adult worms. The presence of a massive infection in the bile ducts gives rise to the syndrome of chronic fascioliasis which is a serious debilitating disease of the host animal. Hitherto liver fluke remedies have been known to kill only the adult and semi-adult worms, and the immature worms have been resistant to attack by such remedies.

It has now been found that the compounds of formula (I) are effective in combatting infections of liver flukes in mammals, and are especially active in combatting infections of worms of Fasciola spp.

In formula (I),

R and R' are the same of different and each is hydrogen, an optionally substituted saturated aliphatic hydrocarbon group having 1 to 7 carbon atoms, or an unsaturated aliphatic hydrocarbon group having 2 to 4 carbon atoms;

R and R are the same or different and each is hydrogen or an alkyl group having 1 to 4 carbon atoms;

Z is the group It is X where m is or 1, and X, X and X are the same or different and each is hydrogen or an alkyl group having 1 to 3 carbon atoms; and A is l) a carbonyldioxy group (-0. CO. 0-) or is a divalent residue of a monocarboxylic acid or a dicarboxylic acid containing 2 to 14 carbon atoms and having two ester linkages, or one ester and one ether linkage, to the rest of the molecule, or is 2) the group O-Y-O where Y is the group where n is O or I, p is 0 or I, and

W is an optionally substituted saturated aliphatic hydrocarbon residue having 1 to 12 carbon atoms, an optionally substituted unsaturated aliphatic hydrocarbon residue having 2 to 12 carbon atoms,

an alicyclic residue having 5 to 10 carbon atoms,

an optionally substituted aromatic residue having 6 to ll] carbon atoms,

an aralkyl residue having 7 to 12 carbon atoms, or a 5- or 6-membered heterocyclic residue.

When R or R is a saturated aliphatic hydrocarbon group it may be substituted by a hydroxy group, an amino group, an N-alkylamino group, an N,N- dialkylamino group, or a carbonyl group for example an acyl group, the alkyl and acyl groups referred to above each having from 1 to 4 carbon atoms.

When R or R is a saturated aliphatic hydrocarbon group having more than two carbon atoms it may be linear or branched alkyl group or a cyclic group such as a cycloalkyl group, but it is preferably a linear (n-)alkyl group; when R or R is an unsaturated aliphatic hydrocarbon group it is preferably an alkenyl group or an alkylalkenyl group, said groups preferably having one ethylenic linkage.

Z is preferably the group --CH .Cl-l

When W is a saturated aliphatic hydrocarbon residue having more than 2 carbon atoms it may be linear or branched and may be substituted by one or more groups, preferably not more than one substituent group on any one carbon atom, for example two hydroxy groups.

When W is an unsaturated aliphatic hydrocarbon residue having more than 2 carbon atoms it may be linear or branched and preferably has one ethylenic linkage.

When W is an aralkyl residue it has the formula tt tiwhere )(",X,)-( and X are the same or different and each is hydrogen or an alkyl group having 1 to 3 carbon atoms, and q and r are the same or different and each is O to 6 provided that both are not 0 and that the sum of q and r is 6 or less.

Preferably W is an alicyclic residue having 5 or 6 carbon atoms, an optionally substituted aromatic residue having 6 to 10 carbon atoms, a S-membered heterocyclic residue containing an oxygen or a sulphur atom, a 6-membered heterocyclic residue containing a nitrogen atom, or a group of the formula where V is a linear saturated aliphatic hydrocarbon residue as hereinbefore defined having 1 to 10 carbon atoms, a linear unsaturated aliphatic hydrocarbon residue as hereinbefore defined having 2 to 10 carbon atoms, or is a benzene residue; X X X and X are the same or different and each is hydrogen or an alkyl group having 1 to 3 carbon atom; and t is O or 1.

Most preferably W is a benzene residue, a linear unsubstituted saturated aliphatic residue having 1 to 7 carbon atoms, or a group of the formula where g is l or 2 and X, X are the same or different and each is hydrogen or a methyl group.

Preferred compounds within formula (I) are those wherein R and R are the same or different and each is hydrogen or a saturated aliphatic hydrocarbon group having I to 4 carbon atoms, and R and R are the same or different and each is hydrogen or methyl.

It will be appreciated by persons skilled in the art that acid addition salts may be formed by those compounds of formula (I) wherein either or both of the groups R and R are saturated aliphatic hydrocarbon groups substituted by an amino, N-alkylamino or N,N- dialkylamino group. Unless the context indicates otherwise, wherever in the following reference is made tocompounds of formula (I) it should be understood that this term includes the acid addition salts of the compounds hereinabove defined.

The compounds of formula (I) have been found active against experimental infections of Fasciola giganlica in mice, and infections of Fasciola hepatica in rabbits and in ruminants including sheep.

The percentage kill of a liver fluke infection by a compound of formula (I) is of course dose dependent. Upon oral administration to sheep infected with F. hepalz'ca an effective flukicidal dose of a compound of formula (I) has been found to lie within the range 40 to 200 mg. per kilogram body weight.

A does of a compound of formula (I) may be followed by a second dose within about 4 weeks, but prac tical considerations would probably dictate its administration after about 5 to 8 weeks. In the case of very light liver fluke infections, the second dose may be delayed for as long as 8 weeks. Since in the field, it must be assumed that animals are continually subject to reinfection, it is especially advantageous in practice to administer these doses regularly during the appropriate season at about 4 to 8 week intervals.

A compound of formula (I) may be used in the treatment of liver fluke infections in mammals including F. hepatica in ruminants including sheep. The compound is preferably administered orally at a dose between 40 and 200 mg. per kilogram.

A compound of formula (I) may be administered for the treatment of liver fluke infections as the raw chemical, but preferably as an ingredient ofa pharmaceutical formulation which contains in addition one or more inert carrier materials commonly used in pharmaceutical formulations as a vehicle for the active ingredient. The preferred formulations are those suitable for oral administration, containing from 5 to 95 percent by weight of a compound of formula (I). If presented as the raw chemical, then a compound of formula (I) is preferably in the form of a powder.

In the context of the present invention, the qualification inert means that the carrier is pharmaceutically acceptable to the host of the infection to which the formulation is administered.

The presentation of an active ingredient (namely, a compound of formula (I) in a pharmaceutical formulation may be as discrete units, such as tablets, capsules or cachets, each containing a predetermined amount of the active ingredient; as a powder or granules; or as a solution or a suspension in an aqueous liquid, a nonaqueous liquid, or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste; in the feed or a feed supplement intended for the host animal; in pellets, salt licks or block licks which are especially suitable for large animals such as sheep.

The formulations may be made by any of the methods of pharmacy but all methods include the step of bringing into association by admixture the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation. The formulations contain one or more of the usual accessory ingredients used to prepare anthelmintic formulations including: solid and liquid diluents (for example, lactose, sucrose, glucose, starches, dicalcium phosphate or calcium phosphate fortablets, granules, dispersible and wettable powders, cachets and capsules; arachis oil, olive oil, or ethyl oleate for soft capsules; water, or vegetable oil for aqueous and nonaqueous suspensions, emulsions, and pastes); binders (for example, starch, sugar, glucose, methyl cellulose, gum acacia, Irish moss or gelatin for granules and tablets); surface active agents (for example sodium lauryl sulphate, cetrimide or polyoxyethylene sorbitan monolaureate for tablets, powders and granules; sodium salt of an alkyl naphthalene sulphonic acid, sorbitan monooleate, ceto-stearyl alcohol and an emulsifier condensate of nonylphenol and ethylene oxide, for pastes and wettable powders); lubricating agents (for example liquid paraffin, talc, stearic acid, magnesium stearate or polyethylene glycol for tablets); dispersing agents (for example, disodium salt of the condensation product of naphthalene sulphonic acid and formaldehyde, and calcium lignin sulphonate for wettable powders, pastes and suspensions); gelling agents (for example colloidal) clays, sulphuric esters of a polysaccharide for aqueous suspensions); suspending and thickening agents (for example gum tragacanth, xanthan gum, alginates polyvinyl pyrrolidone, sodium carboxymethyl cellulose, and hydroxy-ethylcellulose for aqueous suspensions, aqueousbased pastes and wettable powders);

and humectants (for example glycerine for water-based pastes); and other therapeutically acceptable accessory ingredients such as preservatives, buffers and antioxidants, which are known to be useful as carriers in such formulations.

A tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Conveniently each tablet contains from 0.5g. to 4.0g. of the active ingredient.

Granules may be made by the technique of Wet granulation comprising moistening the powdered active ingredient with a binder in an inert liquid, and drying the moist mass; or by the techniques of precompression or slugging. The granules may be administered to animals in an inert liquid vehicle; or in a cachet or capsule of hard or soft gelatin preferably with a liquid or powdered solid diluent; or in a suspension with a water or an oil base. In a drench or suspension, it is preferable to include further accessory ingredients such as a dispersing agent.

A dispersible or wettable powder may be made by admixing together the finely divided active ingredient with a wetting agent, and then administering the powder to the host animal as a suspension or dispersion in water. If desired a dispersing, suspending or thickening agent may be included. These formulations preferably contain from about to 85 percent by weight of the active ingredient.

A paste may be formulated in a liquid diluent which suspends the active ingredient. A stiffening or thicken ing agent may be included, together with a wetting agent and an humectant if the liquid diluent is water. If an emulsion paste is needed (oil-out or water-out), then one or more surface active agents should be included. From about to 80 percent by weight of these paste formulations may be comprised of the active ingredient but if the lower concentrations are used, then sufficient stiffening or thickening agent should be included to provide the desired viscosity.

Suspensions of the active ingredient in an inert liquid carrier are essentially the same as pastes but ofa lower viscosity. They may be formulated using water or other inert diluent as the liquid carrier in association with a dispersingor wetting agent. Other ingredients such as thickening, gelling and suspending agents may also be included. These formulations may contain a wide range of concentrations of active ingredient, but of course, if too high a concentration is included the viscosity of the formulation will increase and the formulation will become more of a paste than a suspension. Subject therefore to the concentration of the remaining ingredients, about 5 to 50 percent by weight of the formulations may be comprised by the active ingredient.

In feed supplements, the active ingredient is generally present in large amounts relative to the accessory ingredients, and the supplements may be added directly or after intermediate blending or dilution. Examples of accessory ingredients for such formulations include solid orally ingestible carriers such as corn meal, attapulgite clay, soya flour, wheat shorts, soya grits, edible vegetable materials, and fermentation residues. The active ingredient is usually incorporated in one or more of the accessory ingredients and intimately and uniformly dispersed by grinding, tumbling or stirring with conventional apparatus. Formulations containing about 1 to 90% by weight of the active ingredient are especially suitable for adding to feeds to provide a concentration desired to control infections by way of the animalss rations.

A compound of formula (I) may be administered either alone as the sole treatment for a liver fluke infection, or in combination with other substances which may complement or supplement its activity. Such additional substances may be administered simultaneously as a separate dose or in combination with a compound of formula (I) in a formulation, and may comprise other anthelmintics having activity against other parasites, such as cestodes (tapeworms) or nematodes. Such additional substances include phenothiazine; piperazine derivatives, for example the citrate, adipate or phosphate salts; organo-phosphorus compounds for ex- 6 ample 0,0-di-(2 chloroethyl) O-(3-chloro-4- methylcaumarin-7-yl)phosphate (Haloxon); 4-t-butyl- 2chlorophenyl Nmethyl O-methylphosphoramidate (Ruelene (Trade Name)); 0,0-diethyl O-(3-chloro-4- methyl-7-coumarinyl)phosphorotlhioate (Coumaphos); 0,0-diethyl O-naphthaloximide phosphate (Naphthalophos); 0,0-dimethyl 2,2,2-trichloro-l-hydroxyethylphosphonate (Trichlorofon); benzimidazole anthelmintics including 2-(4-thiazolyl)benzimidazole (Thiabendazole);methyl S-n-butyl benzimidazole -2- carbamate (Parbendazole); and isopropyl 2-(4- thiazoly)benzimidazolefi-carbamate (Cambendazole); quaternary ammonium anthelmintics including N- benzyl-N, N-dimethyl-N-(2-phenoxyethyl)ammonium salts such as the 3hydroxy-2-naphthoate and embonate salts (Bephenium salts); N, N-dialkyl-4-alkoxy-anaphthamidine anthelmintics including N,N-dibutyl-4- hexyloxy-oz-naphthamidine (Bunamidine); dl-and l-2,3,5,6-tetrahydro- 6-phenylimidazo (2,1-b) thiazole salts (Tetramisole); trans-l-methyl-2- 2-(2- thienyl)vinyl -l ,4,5,6-tetrahydropyrimidine tartrate (Pyrantel tartrate); cis-l,4,5,6-tetrahydro-lmethyl-2- 2-(3-methyl-2-thienyl)vinyl' pyrimidine tartrate (Mo rantel tartrate); polyhalogenated benzanilide anthelmintics including 3,3',5,5,6-pentachloro-2,2'-dihydroxybenzanilide (Oxyclozanide); 2-acetoxy-4- chloro-3, S-diiodobenzanilide Clioxanide); 3,4',5- tribromosalicylanilide (Tribromsalan); 3,5-diiodo-3- chloro-4-(p-chlorophenoxy)salicylanilide (Rafoxa' nide); 5-bromo-2-hydroxy-4'-bromobenzanilide; 2,2-

dihydroxy-3 ,3"-dinitro-5 ,5 -dichloro-biphenyl (Menichlopholan); 2,2'-dihydroxy-3,3',5,5, 6,6'-hexachlorodiphenylmethane (Hexachlorophene); l,4-bis wherein B is a reactive nucleophiliic atom or group and Y and Z are as defined above in formula (I), with an allcali metal salt of a p-hydroxyacylanilide of formula wherein Alk is conveniently potassium or sodium, and D is R or R and E is R or R as defined above in formula (I). In formula (II), B is preferably a halogen atom, for example chlorine, bromine or iodine, or is p toluene-sulphonyloxy, but other alkanesulphonyloxy, arylsulphonyloxy or aralkylsulphonyloxy groups may also be used instead. The reaction is carried out in a liquid medium which is preferably a polar liquid and which conveniently may be an otptionally aqueous alkanol, and is optionally a lower alkanol, for example methanol, ethanol, or isopropanol, or may be dimethylsulphoxide, sulpholane, dimethylformamide, dimethylacetamide, N-methyl-Z-pyrrolidone, or mixtures of the foregoing. If B is chlorine then it is preferable to include a small quantity of postassium iodide in the reaction mixture. The reactants are preferably present in about a 2 to 1 molar ratio of the compounds of formula (III) and (II) respectively, but a slight excess of a compound of formula (III) is conveniently used. The reactants may be heated together under an inert atmosphere, for example nitrogen, at the reflux temperature of the reaction mixture.

It will be appreciated that the compounds of formula (I) most conveniently prepared by this method are those in which R R and R R.

It will of course be understood that in the course of the above reaction the compound of formula (IV) will be formed as a transient intermediate wherein B,Y,Z,E and D are as defined above; andof course a compound of formula (I) may be prepared ab initio by reaction of a compound of formula (IV), with about an equimolar quantity of the compound of formula (III), under the conditions previously described above. It will be further understood that the compounds of formula (I) wherein R differs from R and R differs from R are preferably prepared in this manner.

The compounds of formula (III) identified above may be optionally formed in situ from the corresponding phenol using such basic reagents as sodium hydride, potassium hydroxide, sodium hydroxide, an alkali metal alkoxide, for example potassium tertiary butoxide, sodium ethoxide, sodium methoxide, or a mixture of an alkali metal carbonate and an aliphatic ketone, for example potassium carbonate and acetone.

The compounds of formula (I) may also be prepared by the acylation of an amine of formula (V) wherein R ,R Z and Y are as defined above in formula (I) and both of R are hydrogen or one is hydrogen and the other is the group M.CO where M is one ofR and R as defined in formula (I). The acylation may be carried out by any known means and conveniently in a polar or non-polar liquid medium, the nature of which is dependent upon the acylating agent used. Thus if the acid is used, it is preferred to heat the reactants in excess of the acid. If an acid anhydride is used, then water, an aromatic hydrocarbon, such as benzene, a halogenated aliphatic hydrocarbon such as chloroform, or an ether such as dioxane, may be used as the liquid medium.

An aromatic hydrocarbon or an ether may also be used as the liquid medium if an acid chloride is chosen as the reactant, when the reaction may be effected in the optional presence of a tertiary organic base. An ether, an aromatic hydrocarbon or a halogenated aliphatic hydrocarbon may also be used as the liquid medium if a ketene is used as the acylating agent. The medium may be an excess of the acylating agent above that demanded by the equation of the reaction, for example if using an alkyl ester. The formamido derivatives, that is to say those compounds of formula (I) wherein either or both of R and R are hydrogen, are preferably prepared by the use of formic acid, which may be present in excess to act as a solvent.

The compounds of formula (I) may also be prepared by the reaction of a compound of formula (VI) with a hydroxy-p-Z-oxy-acylanilide of formula (VII) In formulae (VI) and (VII) BD and E are as defined above in formulae (II) and (III), and Y and Z are as defined above in formula (I). The reactants are preferably present in about a 2 to 1 molar ratio the compounds of formula (VVI) and (VI) respectively, but a slight excess of the compound of formula (VII) is conveniently used. The reaction is effected in a liquid medium, desiraby an aprotic liquid, such as toluene, which is preferably anhydrous, and preferably under an inert atmosphere, such as nitrogen; a suitable base, either soluble such as a tertiary organic base (e.g., triethylamine) or insoluble such as an inorganic proton acceptor (e.g., calcium carbonate), is conveniently present, especially when HE is a strong acid.

Included in the definition of B for this method are the hydroxyl and alkoxyl groups. Anhydrous reaction conditions and acidic or basic catalysts are preferably used for both esterification (B OH) and transesterification (B alkoxyl). Non-polar, aprotic solvents are preferred. When B is hydroxyl, a solvent which forms an azeotrope with water is used, e.g., benzene or toluene.

(VII) As an alternative possibility the compound of formula (VI) is reacted with an alkali metal salt of the compound of formula (VII), of the formula (VIII) wherein Alk is conveniently potassium or sodium and Z,D and E are as defined above. The reactants are preferably present in about a 2 to 1 molar ratio'of the compounds of formula (VIII) and (VI) respectively, but a slight excess of the compound of formula (VIII) is conveniently used. The reaction is effected in a liquid medium which is preferably a polar liquid and which conveniently may be a secondary or tertiary alkanol, preferably non-aqueous; for example, isopropanol or tbutanol, or may be dimethylsulphoxide, sulpholane, dimethylformamide, dimethylacetamide, N-methyl-Z- pyrrollidone, or mixtures of the foregoing. The reaction is preferably effected under an inert atmosphere; for example, nitrogen.

It will be appreciated that the compounds of formula (I) most conveniently prepared by the reaction of the (VIII) compounds of formula (VI) with those of formulae (VII) or (VIII) are those in which R R and R R It will be understood that in the course of these reactions the compound of formula (IX) will be formed as a transient intermediate wherein B,D,E,Y and Z are as defined above; and of course a compound of formula (I) may be prepared ab initio by reaction of a compound of formula (VII) or (VIII) with about an equimolar quantity of the compound of formula (IX), under the conditions previously described above. It will further be understood that the compounds of formula (I) wherein R differs from R and R differs from R are preferably prepared in this manner. Also compounds of formula (I) wherein A is connected to the rest of the molecule by one ester and one ether linkages are preferably prepared in this way.

The compounds of formula (VIII) identified above may be optionally formed in situ from the corresponding compound of formula (VII) using such basic reagents as sodium hydride, potassium hydroxide, sodium hydroxide, an alkali metal alkoxide, for example potassium tertiary butoxide, sodium ethoxide, sodium methoxide, or a mixture of an alkali metal carbonate and an aliphatic kctone, for example potassium carbonate and acetone.

The compounds within formula (I) wherein either or both of the groups R and R are saturated aliphatic hydrocarbon groups substituted by an amino, N- alkylamino or N,N-dialkylamino group may also be prepared by the reaction of ammonia or a primary or secondary alkyl amine, as appropriate, with the corresponding halo-substituted compound and this latter may itself be prepared from the amine of formula (V) by haloacylation using, for example, a halo-substituted monocarboxylic acid halide such as monochloracetyl chloride.

Those compounds as hereinabove defined within formula (I) that form acid addition salts may be isolated as such or as the base thereof and may be optionally converted, as appropriate, to the base, an acid addition salt thereof or the salt of another acid by methods known in the art. 7

According to the present invention there are therefore provided the compounds of formula (I); and pharmaceutical formulations comprising the compounds of formula (I) in association with an inert carrier therefor; and methods of making such compounds and such pharmaceutical formulations. The present invention also provides a method for the treatment of infections of liver flukes in mammals comprising the administration to the host of the infection an effective amount of a compound of formula (I).

The present invention is illustrated by the following Examples which should not be construed as in any way limiting the scope of the invention disclosed herein.

EXAMPLE 1 Preparation of bis-(4-acetamidophenoxyethyl)succinate A solution of p-Z-hydroxyethoxyacetanilide (19.5g.) in dry tert-butanol (250 ml.) was made under nitrogen Ill) at room temperature with stirring. Potassium tertbutoxide (1 1.4g.) was added during about 10 minutes, and, after about 1 hr., a solution of succinyl chloride (7.9g.) in dry benzene ml.) was added in a slow stream, half in about 3 minutes, the rest dropwise after about a five minute wait, as the solution had spontaneously warmed. The mixture was left overnight, and was then added to distilled water (500 ml.) and filtered. A thick material precipitated in the filtering flask due to evaporation of benzene. This material was put back on the Buchner funnel with the filtered off solid, and the combination was washed with water and then with dilute sodium carbonate solution, which lightened the color and caused everything to solidify. After washing with water the solid was recrystallized from pyridinewater (about 200 ml. of hot pyridine to dissolve the material, followed by about 200 ml. of water). After about 2 hours at room temperature a nearly white solid was filtered off from the dark mother liquors, m.p. l82l84.2C., insoluble in M sodium carbonate. The mother liquor was stored at 4C. overnight giving a second crop melting at 180.2-l 8I.4C., darker in colour. An analytical sample was prepared by re-crystallization from pyridine-water, m.p. l85-l86.lC.

Analysis for C H N O M.W. 472.48:

Calculated: Found:

C, 6 .00 5.9 C, 6 5.9l;

H, N, 93. H, N, 90.

EXAMPLE 2 push the solid through the stop-cock. Addition took about one-half hour, the internal temperature being kept at 10C. Dry pyridine (25 ml.) was used to wash in the remaining solids, and the mixture was stirred for 2 additional hours, while much yellow precipitate formed. After this time 28 percent ammonia water (13 g.) was added fairly quickly to destroy any remaining phosgene, no obvious reaction occurring. Water (IOOmL) was added with stirring and the mixture stirred for an additional 5 minutes, then filtered. The solid (mp. l77-l83C.) was re-crystallized from ethanolwater, melting point l93.5-l96.5C. It was then dissolved in boiling 95 percent ethanol (about 1 litre), filtered, and water (about 2 litres) was added to incipient turbidity. After four days a yellowish solid was filtered off and a sample dried at l0OC./0.0l mm. of mercury, for analysis. Melting point I98.6I99.4C. (air dried).

Analysis for C ,I-I N O M.W. 416.44:

Calculated: C, 60.56; H, 5.81; N, 6.73. Found: C, 60.56; H, 5.82; N, 7.20,

EXAMPLE 3 Preparation of p-2-hydroxyethoxyacetanilide Method (a) To a solution of potassium tert-butoxide (336 g., 3 moles) in ethanol/tert-butanol (2:1) (1.5

l.)under nitrogen was added a slurry of pacetamidophenol(470 g., 315 moles)in ethanol (250 ml.): the dissolving of the phenol was mildly exothermic and took about 20 minutes. The reaction mixture was then cooled to room temperature and 2- chloroethanol (241.5 g., 3 moles) in ethanol (200 ml.) was added dropwise with stirring. When all the 2- chloroethanol had been added the mixture was heated to just below reflux temperature and maintained at this overnight. The reaction mixture was then filtered while hot (to remove potassium chloride) and upon cooling the filtrate in ice a first crop of product crystallized out. After collecting this crop the filtrate was reduced to half its volume, chilled in ice, and a second crop obtained, m.p. 1 19120C. The product may be recrystallised from 95 percent ethanol or from ethanol-water;

an analytical sample was prepared by recrystallization Calculated: Found:

C. 61.52; H, 6.691N. 7.15 C, 61.57; H, 6.65; N, 7.15

Method (1)) Sodium (4.8 g, 0.21 mole) in approximately 1 g. pieces was added to ethanol (400 ml.) under nitrogen, the resulting exothermic reaction being controlled. When all the sodium had dissolved, a slurry of p-acetamidophenol (30.2 g., 0.2 moles) in ethanol (50 ml.) was added, this addition not being noticeably exothermic. 2-Chloroethanol (16.2 g., 0.2 moles) in ethanol ml.) was then added dropwise and the mixture then heated overnight. The sodium chloride which had precipitated was filtered off, the filtrate concentrated on a steam bath at water pump pressure, and the resulting oil washed with ether. The residual thick liquid crystallized after remaining overnight at C., m.p. 1 18C.

This compound was used in the syntheses described in the foregoing Examples 1 and 2.

EXAMPLE 4 Preparation of bis-(4-acetamidophenoxyethyUazelate By a similar procedure to that of Example 1, bis-(4 acetamidophenoxyethyl)azelate was prepared from the reaction of p-2-hydroxyethoxyacetanilide and azelaoyl chloride. The product was recrystallised from a tert butanol/hexane mixture, m.p. 93.894.8C. (hemihydrate).

Analysis for C H N O 1l/2H O,M.W. (anhydrous)542.6l

Calculated: C, 12.98; H, 7.00, N, 4.73

Found: c, 63.13; H, 7.13; N, 5.08

EXAMPLE 5 Preparation of bis-(4-acetamidophenoxypropyl)succinate By a similar procedure to that of Example 1, bis-(4- acetamidophenoxypropyl) succinate was prepared from the reaction p-3-hydroxypropoxyacetanilide and succinyl chloride. The product was recrystallized from a tert-butanol/n-hexane mixture, m.p. l75.5l79.5C.

Analysis for c H N 0 M.W. 500.53

Calculated C, 62.38; H, 6.44; N, 5.60. Found: C, 62.40; H, 6.75; N, 5.44,

EXAMPLE 6 Calculated: 6 Found: C, 6

int)- EXAMPLE 7 Preparation of bis-(4-acetamidophenoxyethyl) terephthalate Following substantially the procedure of Example 1, bis-(4-acetamidophenoxyethyl) terephthalate was prepared from the reaction of p-Z-hydroxyethoxyacetanilide and terephthaloyl chloride. The product was recrystallized from pyridine, m.p. 259262C. Analysis for (f d-1 N 0 Calculated: C, 64.60; H, 5.42; N, 538 Found: C, 64.91; H, 5.57; N. 5.76.

I claim: 1. The compound of the formula wherein R and R are the same or different and each is hydrogen, a saturated aliphatic hydrocarbon group having 1 to 7 carbon atoms or an unsaturated aliphatic hydrocarbon group having 2 to 4 carbon atoms; R and R are the same or different and each is hydrogen or an alkyl having 1 to 4 carbon atoms; Z is the group where m is 0 or 1, and X, X and X are the same or different and each is hydrogen or an alkyl group having 1 to 3 carbon atoms;

A is 0 --Y 0 and Y is =CO (W) (CO),,

wherein W is an unsubstituted aliphatic hydrocarbon residue having 1 to 12 carbon atoms, and p is 1.

2. The compound according to claim 1 wherein W has 2 to 12 carbon atoms.

3. bis-(4-acetamidophenoxyethyl succinate.

bis-(4-acetamidophenoxyethyl)azelate.

5. bis-(4-acetamidophenoxypropyl) succinate. 

1. THE COMPOUND OF THE FORMULA
 2. The compound according to claim 1 wherein W has 2 to 12 carbon atoms.
 3. bis-(4-acetamidophenoxyethyl succinate.
 4. bis-(4-acetamidophenoxyethyl)azelate.
 5. bis-(4-acetamidophenoxypropyl) succinate. 